Therapeutic composition comprising tetracycline and a dioxolane



United States Patent 3,004,894 THERAPEUTIC COMPOSITION COMPRISINGTETRACYCLINE AND A DIOXOLANE Richard H. Johnson, Kalamazoo, and DonaldP. Wallach, Richland, Mich., assignors to The Upjohn Company, Kalamazoo,Mich., a corporation of Delaware No Drawing. Filed Apr. 7, 1959, Ser.No. 804,577 Claims. (Cl. 167-82) This invention relates to a therapeuticcomposition of tetracycline and more particularly to a parenterallyacceptable dosage form of tetracycline with a dioxolane vehicle.

Prior to the present invention the tetracycline compositions forparenteral administration have utilized water as the vehicle. However,the administration of such aqueous preparations have had thedisadvantages of slow absorption and slow systemic distribution from thesite of injection and trauma and pain at the site of injection.

The therapeutic compositions of the present invention comprisetetracycline and a dioxolane. The compositions can be either solutionsor suspensions depending upon the particular form of tetracycline used,the concentration of the particular tetracycline and the presence ofsolubilizers. Advantageously the compositions can include a parenterallyacceptable acid, a local anesthetic, a compound capable of providing amagnesium ion, and,

as an aid to preparing the composition, a surfactant.

Other antibiotics can be included in the compositions, especiallynovobiocin for its synergistic efiect with tetracycline.

The compositions of the present invention are useful for theadministration of tetracycline and are superior to aqueous tetracyclinecompositions from the therapeutic standpoint in that they produce higherblood levels of tetracycline and are less painful to the patient.

The dioxolane compounds suitable for the compositions of the presentinvention can be represented by the following graphic formula:

R is a hydrogen, methyl or ethyl; R is a hydrogen, methyl, or ethyl; andR is a hydrogen, methyl, carbinol, or ethylol.

The preferred compound is 2,2-dimethyl-l,3-dioxolane- 4-methanol,wherein R and R are methyl and R is carbinol. The other dioxolanecompounds of this group, suitable as a vehicle for tetracycline, are1,3-dioxolane, 4- methyl-l,3-dioxolane, 1,3-dioxolane-4-methanol,1,3-dioxolane-4-ethanol, 2,2-dimethyl-l,3-dioxolane,2,2,4-t1'imethyl-1,3-dioxolane, 2,2-dimethyl-l,3-dioxolane-4-ethanol,2,2-diethyl-l,3-dioxolane, 2,2-diethyl-4-methyl-l,3- dioxolane,2,2-diethyl-1,3-dioxolane-4-methanol,2,2-diethyl-1,3-dioXolane-4-ethanol, 2-methyl-1,3-dioxolane, 2,4-dimethyl-L3-dioxolane, Z-methyl-l,3-dioxolane-4-methanol,2-methyl-l,3-dioxolane-4-ethanol, 2-ethyl-l,3-dioxolane,2-ethyl-4-methyl-1,3-dioxolane, 2-ethyl-l,3-dioxolane-4-methanol,2-ethyl-1,3-dioxolane-4-ethanol, Z-ethyl- 2-methyl-l,3-dioxolane,2,4-dimethyl2-ethy1-1,3-dioxolane,2-ethyl-2-methyl-1,3-dioxolane-4-methanol, 2-ethyl-2-methyl-1,3-dioxolane-4-ethanol.

The term tetracycline as used in the specification and claims hereinshall be taken to include the pharmaceutically and physiologicallyacceptable free base, organic and inorganic salts, as well as chelates,esters, complexes, and

2 6-demethy1 tetracycline and pyrrolidino-methyl-tetracycline.

The solubility of the free base in 2-,2-dimethyl-l,3-dioxolanel-methanolis greater than 250 mg./cc. and the inorganic acid salts such as thehydrochloride or phosphate are more slowly soluble and in concentrationsof more than about 50 mg./cc. form suspensions. Whether the compositionforms a solution or suspension in the dioxolane, however, thecomposition is therapeutically superior to the equivalent aqueouscomposition.

Current medical practice utilizes aqueous compositions having atetracycline concentration of about 50 mg./ cc. and mg./ cc. Thisinvention enables a higher concentration of tetracycline up to 250mg/cc. and more. A concentration greater than 250 mg./ cc. of an insolluble tetracycline increases the viscosity of the compositions andalthough compositions having this increased viscosity are suitable forveterinary purposes Where use of a large needle is permissible, it ispreferred that compositions for human use have a concentration of 250mg./cc. or less. Of course, a lesser concentration can be used tothem'nimum for therapeutic eflicacy.

Although compositions can be prepared having a tetracyclineconcentration from 1 mg. or less/cc. to about 500 mg./cc., it ispreferred to prepare compositions having a concentration which isrelevant to the usual dosage requirements. To this end the compositionsare preferably supplied in unit dosage form, i.e., in single doseamounts of 1 or 2 cc. having 250 mg. of tetracycline or multiple doseamounts of 10 cc. having 2.5 g. of tetracycline.

In addition to the tetracycline, another antibiotic can be included inthe compositions. Advantageously the additional antibiotic can serve toeither broaden the antibacterial speotrum of the composition or exert asynergistic eiiect with the tetracycline against particular bacteria.Novobiocin can be added to the compositions of the present invention tofollowthe preference of current medical practice for the concurrentadministration of tetracycline and novobiocin. Pencillin V can also beincluded with tetracycline in the compositions and the two antibioticscan be present either as separate ingredients or in the form of thetetracycline salt of penicillin V.

A water soluble and parenterally acceptable acid is advantageouslyincluded in the compositions of the present invention wherein thetetracycline is present as the acid addition salt. The addition of anacid to the composition increases further the rapid absorption andsystemic distribution of the antibiotic.

Citric acid is the preferred acid. A concentration of about 10% w./v.citric acid is preferred for those compositions having a tetracyclineconcentration of about 125 mg./cc. Ascorbic acid can also be used aswell as other parenterally acceptable acids such as gluconic acid,lactic acid and glycine hydrochloride.

A local anesthetic'agent is advantageously incorporated into thecompositions of the present invention as a further aid in the reductionof pain'of the injection. The anesthetic eflFect will begin severalminutes after injection and lasts for several hours, onset and durationof action ranging with the particular agent used. A concentration ofabout 0.5 to 2% w./v. is used depending upon the particular localanesthetic agent. local anesthetics such as butethamine, dibucaine,procaine, tetracaine, and lidocaine, as Well as others are suitable. Thehydrochloride salts are usually used for those compositions having anacid present.

Pain can be further reduced by the inclusion of a compound capable ofproviding a magnesium ion, such as magnesium chloride and magnesiumgluconate. Magnesium chloride is used in a preferred concentration ofabout 2 moles or more to 1 mole of tetracycline,

A surfactant in a concentration of about 0.5% is ada 3 vantageouslypresent as an adjuvant to the preparation and administration of thosecompositions forming suspensions. This agent aids in the suspending ofthe insoluble particles in the dioxolane, insuring accurate dosage whenaliquots of the composition are administered. The surfactant alsoprevents freezing of the syringe and clogging of the lumen of thehypodermic needle. Polyoxyethylene sorbitan monolaurate is preferred.

The compositions of the present invention are best prepared in finalform at the time of administration by simply adding the dioxolane fromone container to the dry powder tetracycline mixture in the othercontainer and shaking until dispersed.

In preparing the dry powder mixture the various dry ingredients arefirst reduced to a finely divided state. Examples of the many ways inwhich comminution can be carried out can be found in chapter 11 ofRemingtons Practice of Pharmacy, 11th edition, Mack Publishing Company,Easton, Pennsylvania, U.S.A., 1956. The preferred method of reducing theparticle size of the various ingredients is by use of an air micronizer;particles so reduced by this method will hereinafter be described asmicronized. i

When the final composition is to be a suspension and a surfactant isemployed, the latter is deposited over the surface of the tetracyclineparticles. If the surfactant is fluid, itcan be sprayed 'over thepowder; however, better distribution is obtained if the surfactant isdissolved in a volatile fluid (which is not a solvent for thetetracycline) and the solution sprayed onto the tetracycline.Alternatively, a slurry can be made of the tetracycline and thesurfactant-solvent solution, and the solvent allowed to evaporate. Thecoated teracycline particles are then blended with the remainingingredients until uniformly with the tetracycline powder blend.

. The following examples are illustrative of the process and products ofthe present invention, but are not to be construed as limiting.

' Example 1 I a G, Tetracycline base, milled 287.5a-Diethylamino-2,fi-aceto-xylidide 40 The powders are bolted through No.9 bolting cloth and thoroughly blended. The blended powder mixture is,filled into vials, each vial containing 327,5 mg. of powder mixture. Thevials are sterilized by exposure to ethylene oxide vapors and capped.

Two cubic centimeter glass ampoules are aseptically filled with sterile2,2-dimethyl-1,3-dioxolane-4-methanol and sealed.

At the time for administration the 2,2-dimethyl-1,3-dioxolane-4-methanol is added to the vial containing the antibiotic inan amount sufiicient to make 2 cc. of solution. The vial is shaken untilthe powders are dissolved and the solution withdrawn in a syringe andadministered, preferably intramuscularly; When so used, the prepara:tion gives less pain and higher tetracycline blood levels than anequivalent composition utilizing an aqueous vehicle.

a-Diethylamino-2,6-aceto-xylidide The powders are bolted through No. 9bolting cloth and thoroughly blended. The blended powder mixture isfilled into vials, each vial containing 615 mg. of powder mixture. Thevials are sterilized by exposure to ethylene oxide vapors and capped.

Two cubic centimeterlglass ar'npoules are aseptically filled with Vsterile 2;,2-dimethyl-1,3-dioxolane-4-methanol and sealed. 7 7

At the time for administration the 2,2-dimethyl-1,3-dioxolane-4-methanolis added to the vial containing the antibiotic in an amount sufficientto make 2 cc. of solution. The vial is shaken until the powders aredissolved and the solution withdrawn in a syringe and administered,preferably intramuscularly. Whenso used, the preparation gives less painand higher tetracycline blood levels than an equivalent compositionutilizing an aqueous vehicle.

Example 3 G. Tetracycline base, milled 287.5 Calcium acid novobiocin,micronized 143.7 a-DiethyIaminO-Z,6-aceto-xylidide 40 The powders arebolted through No. 9 bolting cloth and thoroughly blended. The blendedpowder mixture is filled into vials, each vial containing 471.2 mg. ofpowder mixture. The vials are sterilized by exposure to ethylene oxidevapors and capped.

Two cubic centimeter glass ampoules are aseptically filled with sterile2,2-dimethyl-1,3-dioxolane-4-methanol and sealed.

' At the time for administration the 2,2-dimethyl-1,3-dioxolane-4-methanol is added to the vial containing the antibiotics inan amount s-ufiicient to make 2 Co. The vial is shaken to uniformlydistribute the antibiotics and the final compositions withdrawn in asyringe and administered, preferably intramuscularly. When so used, thepreparation gives less pain and higher tetracycline blood levels than anequivalent composition utilizing an aqueous vehicle.

Example 4 Tetracycline phosphate, micronized, 1%. lecithin coated 287.5Citric acid anhydrous, micronized 222 a-Diethylamino 2,6-aceto-xylididehydrochloride,

micronized 44 The dry powders are mixed together until uniformlydispersed. 553.5 mg. of the mixture are filled into a vial, sterilizedwith ethylene oxide and capped.

1.9 cc. of sterilized 2,2-dimethyl-1,3-dioxo1ane-4-methanol isaseptically filled into a glass vial and sealed.

At the time for administration the 2,2-dimethyl-l,3-

. dioxolane-4-methanol is added to the vial containing the antibiotic inan amount suflicient to make 2 cc. of suspension, The vial. is shaken tosuspend the antibiotic and the suspension withdrawn in a syringe andadministered, preferably intramuscularly. When so used, the preparationgives less pain and higher tetracycline blood levels than, an equivalentcomposition utilizing an aqueous vehicle. 4

The polyoxyethylene sorbitan is dissolved in about 250 cc. of chloroformand the solution mixed with the tetracycline until the tetracyclineparticles are uniformly wetted. The chloroform is allowed to evaporateand the cake dried at 40 C. for 2 hours. The tetracycline cake iscomminuted and the powder blended With the remaining ingredients. 561.5mg. of the mixture is filled into a vial, sterilized with ethyleneoxide, and capped.

1.9 cc. of 2,2-dimethyl-1,3-dioxolane-4-methanol is aseptically filledinto a glass vial and sealed.

At the time for administration the 2,2-dimethyl-l,3-dioxolane-4-methanol is added to the vial containing the antibiotic inan amount suflicient to make 2 cc. of suspension. The vial is shaken tosuspend the antibiotic and the suspension withdrawn in a syringe andadministered, preferably intramuscularly. When so used, the preparationgives less pain and higher tetracycline blood levels than an equivalentcomposition utilizing an aqueous vehicle.

Example 6 G. Tetracycline phosphate, micronized 287.5 Citric acid,anhydrous, micronized 220 Tetracaine hydrochloride, micronized 44Polyoxyethylene sorbitan monolaurate 10 The polyoxyethylene sorbitan isdissolved in about 250 cc. of chloroform and the solution mixed with thetetracycline until the tetracycline particles are uniformly wetted. Thechloroform is allowed to evaporate and the cake dried at 40 C. for 2hours. The tetracycline cake is comminuted and the powder blended withthe remaining ingredients. 561.5 mg. of the mixture is filled into avial, sterilized with ethylene oxide and capped.

1.9 cc. of sterilized 2,2-dimethyl-1,3-dioxolane-4-methanol isaseptically filled into a glass vial and sealed.

At the time for administration the 2,2-dimethyl-1,3- dioxolane-tmethanolis added to the vial containing the antibiotic in an amount sufficientto make 2 cc. of suspension. Ihe vial is shaken to suspend theantibiotic and the suspension withdrawn in a syringe and administered,preferably intramuscularly. When so used, the preparation gives lesspain and higher tetracycline blood levels than an equivalent compositionutilizing an aqueous vehicle.

The polyoxyethylene sorbitan is dissolved in about 250 cc. of chloroformand the solution mixed with the tetracycline until the tetracyclineparticles are uniformly wetted. The chloroform is allowed to evaporateand the cake dried at 40 C. for 2 hours. The tetracycline cake iscomminuted and the powder blended with the remaining ingredients. 561.5mg. of the mixture is filled into a vial, sterilized with ethylene oxideand capped.

1.9 cc. of sterilized 2,2-dimethyl-1,3-dioxolane-4-rncthanol isaseptically filled into a glass vial and sealed.

At the time for administration the 2,2-dimethy1-1,3-dioxolane-4-methanol is added to the vial containing the antibiotic inan amount suflicient to make 2 cc. of suspension. The vial is shaken tosuspend the antibiotic and the suspension withdrawn in a syringe andadministered, preferably intramuscularly. When so used, the preparationgives less pain and higher tetracycline blood levels than an equivalentcomposition utilizing an aqueous vehicle.

The polyoxyethylene sorbitan is dissolved in about 500 cc. of chloroformand the solution mixed with the tetracycline until the tetracyclineparticles are uniformly wetted. The chloroform is allowed to evaporateand the cake dried at 40 C. for 2 hours. The tetracycline cake iscomminuted and the powder blended with the remaining ingredients. 774mg. of the mixture is filled into a vial, sterilized with ethylene oxideand capped.

p 1.9 cc. of 2,2-dimethyl-1,3-dioxolane-4-methanol is aseptically filledinto a glass vial and sealed.

At the time for administration the 2,2-dimethyl-1,3-dioxolane-4-methanol is added to the vial containing the antibiotic inan amount sufficient to make 2 cc. of suspension. The vial is shaken tosuspend the antibiotic and the suspension withdrawn in a syringe andadministered, preferably intramuscularly. When so used, the preparationgives less pain and higher tetracycline blood levels than an equivalentcomposition utilizing an aqueous vehicle.

Example 9 G. Tetracycline phosphate, micronized 575 Polyoxyethylenesorbitan monolaurate 10 The polyoxyethylene sorbitan monolaurate isdissolved in about 500 cc. of chloroform and the solution mixed with thetetracycline until the tetracycline particles are uniformly wetted. Thechloroform is allowed to evaporate and the cake dried at 40 C. for 2hours. The tetracycline cake is comminuted. 5 mg. of the powder isfilled into a vial, sterilized with ethylene oxide and capped.

1.9 cc. of 2,2-dimethyl-1,3-dioxolane-4-methanol is aseptically filledinto a glass vial and sealed.

At the time for administration the 2,2-dimethyl-l,3- dioxolane-tmethanolis added to the vial containing the antibiotic in an amount sufficientto make 2 cc. of suspension. The vial is shaken to suspend theantibiotic and the suspension withdrawn in a syringe and administered,preferably intramuscularly. When so used, the preparation gives lesspain and higher tetracycline blood levels than an equivalent compositionutilizing an aqueous vehicle.

Example 10 G 6-demethyl tetracycline, milled 287.5u-Diethylamino-2,6-aceto-xylidide 40 The powders are bolted through No.9 bolting cloth and thoroughly blended. The blended powder mixture isfilled into vials, each via'l containing 325.5 mg. of powder mixture.The vials are sterilized by exposure to ethylene oxide vapors andcapped.

1.9 cc. of sterilized 2,2-climethyl-l,3-dioxolane-4-methano] isaseptically filled into a glass vial and sealed.

At the time for administration the 2,2-dimethyl-l,3-dioxolane-4-methanol is added to the vial containing the antibiotic inan amount suflicient to make 2 cc. The vial is shaken to disperse theantibiotic and the composition withdrawn in a syringe and administered,preferably in tramuscularly. When so used, the preparation gives lesspain and higher tetracycline blood levels than an equivalent compositionutilizing an aqueous vehicle.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art, and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A therapeutic composition for parenteral administration comprisingtetracycline as an essential active ingredient and, as a vehicletherefor, 2,2-dimethyl-l,3-diox- =olane-4-methanol.

2. The composition of claim 1 wherein the tetracycline is thetetracycline free base.

3. The composition of claim 1 wherein the tetracycline is a acidaddition salt of tetracycline free base.

4. The composition of claim 1 wherein the tetracycline is the penicillinV salt of tetracycline free base.

5. The composition of claim 1 whereinthetetracycline is G-demethyltetracycline. t

6. The composition of claim 1 wherein the tetracycline ispyrrolidino-methyl-tetracycline.

7. A therapeutic composition for parenteral administration comprising apharmacologically acceptable acid addition salt of tetracycline freebase as an essential active ingredient, a non-toxic, parcnterallyacceptable, Water soluble acid/and, as a vehicle therefor, 2,2-dimethyll,3 -dioxolane-4-methanel.

8. A therapeutic composition for parenteral administration comprisingfrom' about 5 mg./cc. to about 5.00 nag/cc. of tetracycline as anessential active ingredient, and, as a vehicle therefor,2,2-dimethyl-1,3-dioxolane-4- methanol. 7.

9. A therapeutic composition for parenteral administration comprisingabout 12.5% tetracyclinephosphate, about 10% citric acid, about 2.0%a-diethylamino-2,6- aceto-Xylidide hydrochloride, about 0.5%polyoxyethylene sorbitan monolaurate and 2,2-dimethyl-1,3-dioxolane-4-rnethanol.

10. A therapeutic composition for parenteral administration comprisingabout,12,5% tetracycline phosphate,-

about 10% citric. acid, about 2. 0%' tetracaine hydrochloride, about 0.5polyoxyethylene sorbitan monolaurate and2,2-dimethyh1,3-diox0lane-4-methanol.

ReferencesCited in the fileof this patent UNITED STATES PATENTS2,428,805 Kharasch Oct. 14, 1947 FOREIGN PATENTS 279,099 SwitzerlandMar. 1, 1952 535,471 Canada Jan. 8, 1957 793,558 Great Britain Apr. 16,1958 OTHER REFERENCES UNITED STATES PATENT OFFICE M CERTIFICATE OFCORRECTION Patent N0. 3,004,894 October 17, 1961 Richard H. Johnson etalo It is hereby certified that error appears in the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 3, line 33 for "teracycline" read tetracycline line 56, for "327,5 mg.

read 327.5 mg column 5 l ne 68 for "200" read 220 column 6 line 73 after"is a" lnsert pharmacologically acceptable Signed and sealed this 10thday of April 1962.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Commissioner of Patents Attesting Officer

1. A THERAPEUTIC COMPOSITION FOR PARENTERAL ADMINISTRATION COMPRISINGTETRACYCLINE AS AN ESSENTIAL ACTIVE INGREDIENT AND, AS A VEHICLETHEREFOR, 2,2-DIMETHYL-1,3-DIOXOLANE-4-METHANOL.